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Cochrane Review: Green et al, Cochrane Review: Green et al,
The Lancet’ 01
Canadian MetaCanadian Meta--analysis : Lukka analysis : Lukka
et al,et al, Clin Oncol’ 02
Green et al metaGreen et al meta--analysis on analysis on
concurrent concurrent chemoradiationchemoradiation: :
Update Cochrane Database Syst Rev,
2005;Jul 20: (3)
Wong, Gynecol Oncol’ 89
Tseng, Rose, Keys, Morris, Peters, Whitney
NCI Clinical Announcement’ 1999
Pearcey, Proc ASCO’ 00 [abst]
Green Meta-analysis, The Lancet’ 01
Lukka Meta-analysis, Clin Oncol’ 02
Green Meta-analysis UpdateCochrane Database Syst Rev’05
Chemo-Radiation in Advanced Stage Carcinoma Cervix
4/6/2010 2
AUTHOR ARMS RESULTS COMMENTS CRITICISMS
Whitney et al. 1999(GOG-85)
IIB-IIIB
RT+Cisplatin / 5FU Vs.
RT+HU
OS-55%Vs.
43%
Better PFS and OS than HU with manageable
toxicity
1. Comparison of two CTRT regimens
2. No RT alone arm3. Sub optimal
(81Gy to pt A)4. protracted RT
(median duration 63 days)
Morris et al. 1999 (RTOG
9001) IB- IVA
RT+CisplatinVs.
5FU + RT
OS-73%Vs.
58%
CT had a survival advantage with
decrease in both LR and distant failure
1. RT optimal, 89Gy to pt A, 58 days
2. Survival benefit in IB-IIB, not in adv stage
Keys et al. 1999
(GOG-123) Bulky IB
RT+Cisplatin+ SXVs.
RT+ SX
OS-83%Vs.
74%
Significant differences in PFS and OS favoring
CTRT
1. Suboptimal RT dose
2. Trial for pre op regimen IB only
Critical Review of 5 trials
4/6/2010 3
AUTHOR ARMS RESULTS COMMENTS CRITICISMS
Peters et al. 2000
IA2-IIA
SX+RT+Cisplatin/5 FU Vs.
SX+RT
OS-80%Vs.
63%
Survival favored the chemoradiotherapy arm
1. Post op RT, no brachy
2. Early stage
Rose et al. 1999
(GOG 120) IIB-III-
IVA
RT+CisplatinVs.
RT+Cisplatin/5FU/H U
Vs. RT+HU
PFS–67% Vs.
64%Vs.
47%
Superiority of concomitant CTRT regimen with cis alone
was less toxic then 3 drug regimen
1. No RT alone arm2. Comparison of 3
ctrt regimens3. Low total RT dose &
protracted Rx time
‘‘CONCURRENT CHEMORADIATION FOR CERVICAL CANCERCONCURRENT CHEMORADIATION FOR CERVICAL CANCER’’
in February 1999in February 1999
““Five major randomized phase III trials show that platinum based Five major randomized phase III trials show that platinum based chemo chemo when given concurrently with RT prolongs survival in women with when given concurrently with RT prolongs survival in women with locally locally
advanced cervical cancer stages Ib2 advanced cervical cancer stages Ib2 -- IVa as well as in women with stage IVa as well as in women with stage I / IIa found to have metastatic pelvic lymph nodes, positive paI / IIa found to have metastatic pelvic lymph nodes, positive parametrial rametrial disease and positive surgical margins at the time of primary surdisease and positive surgical margins at the time of primary surgerygery ””
BACKGROUND AND RATIONALE
NATIONAL CANCER INSTITUTE CLINICAL ANNOUNCEMENT
NATIONAL CANCER INSTITUTE CLINICAL ANNOUNCEMENT
Cochrane Collaborative Group (19 Trials) Meta Meta -- analysisanalysis
19 RCTs between 1981 and 2000 : 4580 pts19 RCTs between 1981 and 2000 : 4580 ptsIncrease in OAS by 12% & RFS by 16% (absolute Increase in OAS by 12% & RFS by 16% (absolute benefit) (p=0.0001)benefit) (p=0.0001)
Greater benefit in patients in stages IB2 and IIBGreater benefit in patients in stages IB2 and IIB
Decrease in local and systemic recurrence (p=0.0001)Decrease in local and systemic recurrence (p=0.0001)
Green JA et al Lancet 358;781 (Sept. 2001)
• Update in July 2005: 21 trials and 4921 pts• Similar findings (absolute benefit: 10%)• Test for Heterogeneity : Positive • No data on late toxicities
Cochrane Database Syst Rev. 2005 Jul 20;(3):CD002225.
Cisplatin based Concomitant Chemo-radiation
Significant improvement in Overall Survival
- Advanced Stages (Only 30% tumors)
- Bulky IB tumors (prior to surgery)
- High risk early disease (post-surgery)
Toxicities Acute Grade 3/4 Hematological and G.I significantly higher : all short lived
2 deaths due to the toxicities
No significant late toxicities seen
Canadian Group (9 Trials) - 4 year survival data Meta-analysis
Lukka et al, Clinical Oncology 14;203(June 2002)
Heterogenous patient data
Suboptimal Radiotherapy Schedules Used
Non-uniform use of CT drugs and Sequencing
QOL issues : Unknown
Cost effectiveness ?
Hence Concomitant chemo-radiation needs to be tested
optimally in our setting
Sparse literature form Developing Countries
Critical Review of Trials Chemo-radiation in Carcinoma Cervix
Chemo-Radiation in Advanced Stage Carcinoma Cervix
(FIGO IIIB): A Phase III Randomized Trial (CRACx Trial)
HSRC / HEC Project No: 114/2003
Clinicaltrials.gov ID : NCT00193791
Protocol ID : TMH/114/2003/CRACx TRIAL
TMC Cervix Working Group
425 patients
Radical Radiotherapy Ext RT+ICA
50 Gy(MLB at 40)/5wks + LDR/HDR
LDR: 30Gy or HDR: 7Gyx3#
425 patientsConcomitant chemotherapy
weekly Cisplatin and
Radiotherapy
• Hypothesis: Improvement in OAS by 10% (35% to 45%)
• Power of detection: 80% (alpha error: 0.05)
• Intent to treat basis
• Accrual Period: 5-6 years
• Interim analysis : Twice One at 50 % and another at 75 % event rates
Carcinoma Cervix Stage FIGO IIIBCarcinoma Cervix Stage FIGO IIIB
Chemo-Radiation in Advanced Carcinoma Cervix (CRACx Trial ): 2003
Aims & ObjectivesAims & ObjectivesAims & Objectives
Primary1.1. To compare the overall and disease free survivals To compare the overall and disease free survivals
2.2. To compare acute toxicitiesTo compare acute toxicities
3.3. To evaluate single agent chemotherapy To evaluate single agent chemotherapy ‘‘CisplatinCisplatin’’
Secondary1.1. To compare distant metastasis rate.To compare distant metastasis rate.
2.2. To compare late toxicities in both groups.To compare late toxicities in both groups.
Chemo-Radiation in Advanced Carcinoma Cervix (CRACx Trial )
Pre-treatment EvaluationPre-treatment Evaluation
Pelvic Examination / EUA (Pelvic Examination / EUA (sossos) / ) / GynaeGynae Joint ClinicJoint Clinic
Complete Blood Profile Complete Blood Profile
Serum Biochemistry (Serum Biochemistry (Liver+RenalLiver+Renal functions+ Electrolytes)functions+ Electrolytes)
Chest XChest X--RayRay
USG (A + P) / CT Scan (A+P) : OptionalUSG (A + P) / CT Scan (A+P) : Optional
ECGECG
CystoscopyCystoscopy: if indicated.: if indicated.
Chemo-Radiation in Advanced Carcinoma Cervix (CRACx Trial )
Inclusion CriteriaInclusion Criteria
Squamous carcinoma Squamous carcinoma
Performance index WHO Grade 0 or 1Performance index WHO Grade 0 or 1
Age < 65 years Age < 65 years
FIGO stage IIIBFIGO stage IIIB
Normal ECG and Cardiovascular systemsNormal ECG and Cardiovascular systems
Normal hematological parameters.Normal hematological parameters.
Normal renal & liver function test.Normal renal & liver function test.
Chemo-Radiation in Advanced Carcinoma Cervix (CRACx Trial )
Exclusion CriteriaExclusion Criteria
CoCo--morbid conditions like medical renal disease.morbid conditions like medical renal disease.
Medical or psychological condition that would preclude Rx.Medical or psychological condition that would preclude Rx.
History of previous treatment.History of previous treatment.
Patient unreliable for treatment completion & followPatient unreliable for treatment completion & follow--up.up.
• External RT : Whole Pelvis with AP/PA or four field box technique• Dose : 50 Gy / 25 # / 5 Weeks (40 Gy open + 10 Gy with MLB)
• Brachytherapy :
Chemo-Radiation in Advanced Carcinoma Cervix (CRACx Trial )
LDR : 30 Gy X 1 # to pt A Or
HDR : 7 Gy X 3 # to pt A
• Chemotherapy Patient randomised to CT+ RT
receive Inj. Cisplatin 40 mg/m2 wkly
Treatment ProtocolTreatment Protocol
Evaluation of Response & ToxicityEvaluation of Response & ToxicityEvaluation of Response & Toxicity
Response :Response : WHO CriteriaWHO Criteria
Toxicity ScoringToxicity Scoring
Acute toxicities : CTC version 2.0Acute toxicities : CTC version 2.0
Late toxicities : RTOG / LENTLate toxicities : RTOG / LENT--SOMA scoring criteria.SOMA scoring criteria.
Follow Up :Follow Up :
Clinical examination, Assessment of tumor response, late Clinical examination, Assessment of tumor response, late
complications & relevant investigations / Rx will be done accordcomplications & relevant investigations / Rx will be done accordinglyingly
11stst followfollow--up: 6 up: 6 --10 weeks 10 weeks
Subsequently every 3 Subsequently every 3 -- 4 mths for the first 2 years.4 mths for the first 2 years.
6 monthly thereafter 6 monthly thereafter
Chemo-Radiation in Advanced Carcinoma Cervix (CRACx Trial )
Chemo-Radiation in Advanced Carcinoma Cervix (CRACx Trial )
ACCRUAL DETAILS
• Study Started : August 2003
• Pts randomised till Nov. 2008 : 627 pts
• Audit of pts till Dec. 2007 : 528 pts
• Planned Accrual Completion : Dec 2009
• Interim Analysis : Jan 2010
• Final Analysis : Dec 2011
Chemo-Radiation in Advanced Carcinoma Cervix (CRACx Trial )
AUDIT
• Audit of pts till Dec. 2007 : 528 pts
• RT Alone : 255 pts
• CT + RT : 263 pts
• Randomization : Computerized (open label)
• Analysis : ITT
Cisplatin Chemotherapy Compliance Cisplatin Chemotherapy Compliance
No of CyclesNo of Cycles No of pts (263 pts)No of pts (263 pts)
6#6# 0303
44--5#5# 226 (4#: 43 pts)226 (4#: 43 pts)
3#3# 1717
2#2# 7 (1pt had single kidney)7 (1pt had single kidney)
00--1#1# 10 (Incomplete Rx)10 (Incomplete Rx)
Chemo-Radiation in Advanced Carcinoma Cervix (CRACx Trial )
Chemo-Radiation in Advanced Carcinoma Cervix (CRACx Trial )
RESPONSE RATES (6-10 weeks Post Rx)RESPONSE RATES (6-10 weeks Post Rx)
RT AloneRT Alone
255 pts255 pts
CT + RTCT + RT
263 pts263 pts
CRCR 229229 227227
PRPR 0808 1414
ProgProg. Disease. Disease 0505 0606
Not assessed*Not assessed* 1313 1616
* 6-10 weeks Post Rx not completed
ACUTE TOXICITIES
RT AloneRT Alone255 pts255 pts
CT + RT*CT + RT*263 pts263 pts
GIGI GrGr IIIIGrGr IIIIII
686812 (4.7%)12 (4.7%)
787817 (7%)17 (7%)
GU GU GrGr IIIIGrGr IIIIII
151510 (4%)10 (4%)
232315 (5.7%)15 (5.7%)
SkinSkin GrGr IIIIGrGr IIIIII
63632929
63632626
AnemiaAnemia GrGr IIIIGrGr IIIIII
24245 (2%)5 (2%)
10110115 (5.7%)15 (5.7%)
NeutropeniaNeutropenia GrGr IIIIGrGr IIIIII
060602 (0.7%)02 (0.7%)
393909 (3.5%)09 (3.5%)
ThrombocytopeniaThrombocytopenia GrGr IIIIGrGr IIIIII
010102 (0.7%)02 (0.7%)
161609 (3.5%)09 (3.5%)
* 1 pt Dyselectrolytemia and death & 2 pt Gr IV Oto-toxicity (Irreversible)
Chemo-Radiation in Advanced Carcinoma Cervix (CRACx Trial )
RT ALONERT ALONE(255 pts)(255 pts)
CT + RTCT + RT(263 pts)(263 pts)
Recurrences Recurrences 4747 3838
Progressive Disease Progressive Disease LocoLoco--regional Recurrence regional Recurrence LR + Distant Recurrence LR + Distant Recurrence
Distant Mets Distant Mets
0404131307072323
0404111104 04 1919
Died due to Rx Complications Died due to Rx Complications 01 (Unknown)01 (Unknown) 0101
Lost to followLost to follow--up (after 1up (after 1-- 2 FU)2 FU) 1616 1212
N= 486 pts: Follow-up: Median: 24 months (3 - 48 months)
Chemo-Radiation in Advanced Carcinoma Cervix (FIGO IIIB) (CRACx Trial )
* Acute Gr II/III Genitourinary/hematological toxicities higher in CT+ RT arm
* Grade II / III Procitiits seen in 7 pts in each arm so far
Ongoing
Chemo-Radiation in Advanced Carcinoma Cervix (CRACx Trial )
AUDIT SUMMARY
• Acute Grade III GI and Hematological toxicities : Higher with CT+ RT
• Recurrence event rates comparable so far
• Late toxicities yet to evaluated
• Cost benefit analysis – most critical in our setting
• Completion of accrual and outcome analysis
• Report on 1st Interim Analysis : Jan 2010
Thank You